UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors
Abstract
Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of UFL1 or UBA5 , or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Yongkang Zou
Institute of Cancer Research, Shenzhen Bay Laboratory
Zhaoxiang Wang
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Qiang Jiang
Department of Animal Genetics, College of Animal Science and Technology, Nanjing Agricultural University
Xia Kong
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Xiaohe Ma
Zhengyan Liang
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Zhiguo Wang
Department of Cell Biology, School of Basic Medicine, Hangzhou Normal University
Beiying Chen
Department of Cell Biology, School of Basic Medicine, Hangzhou Normal University
Jiao Yuan
Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University
Jiayue Wen
Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University
Sheng Ye
School of Artificial Intelligence
Yubin Yan
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Binbin Li
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Xing-dong Xiong
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Xin-guang Liu
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Zhiwei He
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University
Yafei Cai
Department of Animal Genetics, College of Animal Science and Technology, Nanjing Agricultural University
Junzhi Zhou
Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University